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In 1999,
a working group of 21 representatives from major academic medical centers
and research, government, military, public health, and emergency management
institutions and agencies developed consensus-based recommendations for
measures to be taken by medical and public health professionals following
the use of smallpox as a biological weapon on civilian populations. Their
consensus recommendations covered five main areas:

These recommendations
and a brief overview of smallpox disease are presented below. This information
is taken from an article published under the same title in the June 9,
1999, issue of the Journal of the American Medical Association.

Historical
Perspective/Background

The occurrence
of smallpox was once worldwide in scope. A global campaign, begun in
1967 under the auspices of the World Health Organization (WHO), succeeded
in eradicating naturally acquired smallpox in 1977. In the United States,
routine vaccination ceased in 1972.

Before
1972, smallpox vaccination was recommended for all U.S. children at
1 year of age. Most states required evidence of vaccination for school
entry. Vaccination was also required for military recruits and tourists
visiting other countries. Few persons younger than 34 years have been
vaccinated. In 1998, the U.S. Census reported approximately 114 million
persons were age 29 years or younger and, most likely, not vaccinated
against smallpox.

WHO proposed
in 1986 that all laboratories destroy their variola stocks or transfer
them to one of two WHO reference labs: the Institute of Virus Preparations
in Moscow, Russia, or the Centers for Disease Control and Prevention
in Atlanta, Georgia. All countries reported compliance. However, it
was reported that, beginning in 1980, the Soviet government embarked
on a successful program to produce smallpox virus in large quantities
and adapt it for use in weapons. This report is cause for some concern
because funding for Russian labs has declined and existing expertise,
stocks, and equipment could migrate to other countries.

Forms
of the Disease

Smallpox
is a DNA virus, a member of the genus orthopoxvirus. There are two epidemiologically
distinct types of variola—major and minor—based largely on mortality
rates. Variola minor is in some cases caused by a virologically distinct
virus (variola "alastrim" minor), and in other situations
is speculated to have been "minor" because of the population
(immunity) status.

In general,
the illness associated with variola minor is milder with a sparse rash.
Pre-eruptive or prodromal stages of major and minor are similar, but
constitutional symptoms after rash onset are less severe in minor than
in major. Although the quantity of lesions in minor could equal the
number seen in a major case, flatpox forms of disease were not seen
with variola minor, and hemorrhagic forms were rare. A more rapid evolution
of rash, over 6 to 7 days to crust stage, is observed in variola minor.
Secondary fevers, common in variola major, are less frequently seen
in variola minor. Ultimately, an outbreak of variola minor could be
differentiated from variola major only after evaluation of the mortality
rate. Outbreaks of minor had mortalities of ~1%. A milder form of disease
is also seen among those who have residual immunity from prior vaccination.
In partially immune persons, the rash tends to be more scant and evolution
of lesions more rapid.

Two rare
forms of smallpox that can be difficult to recognize are hemorrhagic
and malignant or flat-type. Both are characterized by a somewhat shorter
incubation period and severely prostrating prodromal illness with fever,
headache, and backache. Hemorrhagic smallpox is uniformly fatal; pregnant
women appear to be unusually susceptible. Death usually occurs on the
fifth or sixth day after the onset of rash. Malignant smallpox is frequently
fatal. Constitutional symptoms are similar, but lesions develop slowly
and do not progress to the pustular stage, remaining soft, flat, and
velvety to the touch. If the patient survives, the lesions disappear
without forming scabs, or, in severe cases, large amounts of skin may
peel away.

Transmission

Natural
infection occurs following implantation of the virus on the otolaryngeal
or respiratory mucosa. The infectious dose is unknown but believed to
be only a few virions.

Smallpox
spreads from person to person primarily by droplet nuclei or aerosols
expelled from the oropharynx of infected persons and by direct contact.
Contaminated clothing or bed linens can also spread the virus. There
are no known animal or insect vectors.

The risk
for transmission does not occur until the onset of rash, following a
period of high fever and malaise. Secondary cases are most often seen
in those immediately caring for the patient, who is most infectious
from the onset of the rash through the first 7 to 10 days of the rash.
As scabs form, the risk of infecting others rapidly wanes. Even though
scabs contain large amounts of viable virus, it appears not to be especially
infectious, presumably because the virions are tightly bound in the
fibrin matrix.

Clinical
Presentation

Following
infection, the virus migrates to the regional lymph nodes and multiplies.
The patient develops asymptomatic viremia on about the third or fourth
day, followed by multiplication of the virus in the spleen, bone marrow,
and lymph nodes. Secondary viremia begins on about the eighth day, followed
by fever and toxemia. The virus, contained in leukocytes, then localizes
in small blood vessels of the dermis and beneath oral and pharyngeal
mucosa and subsequently infects adjacent cells.

At the
end of the 12-to-14-day incubation period (range: 7 to 17 days), the
patient typically experiences high fever, malaise, and prostration with
headache and backache. Severe abdominal pain and delirium are sometimes
present. A maculopapular rash then appears on the mucosa of the mouth
and pharynx and on the face and forearms; the rash then spreads to the
trunk and legs. Within 1 to 2 days, the rash becomes vesicular and,
later, pustular. Pustules are characteristically round, tense, and deeply
embedded in the dermis. Crusts begin to form on about day 8 or 9. As
the patient recovers, the scabs separate and characteristic pitted scarring
gradually develops.

The rash
is centrifugal in distribution, most dense on the face and extremities.
Lesions develop during a 1-to-2-day period and evolve at the same rate.
On any given part of the body, they are generally at the same stage
of development. This characteristic is in contrast with chickenpox (varicella),
the disease most often confused with smallpox. With varicella, new lesions
appear in crops every few days, and lesions at very different stages
of maturation can be adjacent; varicella lesions are more concentrated
on the trunk than on the face and extremities and are almost never found
on the palms and soles. http://emergency.cdc.gov/agent/smallpox/images/smpxman1.gif

Except
for lesions in the skin and mucosa and reticulum cell hyperplasia, other
organs are seldom involved. Secondary bacterial infection is not common.
Death, most common during the second week of illness, most likely results
from the toxemia associated with circulated immune complexes and soluble
variola antigens. Encephalitis sometimes ensues and is indistinguishable
from the acute perivascular demyelination observed as a complication
of infection.

Neutralizing
antibodies can be detected by day 6 of the rash and remain at high titers
for many years. Hemagglutinin-inhibiting antibodies can also be detected
about day 6 of the rash or about 21 days after infection, and complement-fixing
antibodies appear about 2 days later.

Diagnosis/Laboratory
Confirmation

Laboratory
confirmation of the diagnosis is important. Visualization of an orthopoxvirus
particle, to suggest a diagnosis of smallpox infection, can be quickly
accomplished by electron microscopic examination of vesicular or pustular
fluid or scabs.

Specimen
collection should be done by personnel who are knowledgeable and who
have been vaccinated. Contact precautions should be observed, with the
additional use of a facemask. Guidance for proper specimen collection
procedures can be obtained from the CDC.

State
and local health department labs should be immediately contacted, as
examination requires high-containment facilities and should be undertaken
only by those with appropriate training and equipment. Definitive lab
identification and characterization of the virus involves growing the
virus in cell culture or on chorioallantoic egg membrane and performing
various biologic assays, including PCR (polymerase chain reaction) technique
and restriction fragment-length polymorphisms. PCR studies can be completed
within a few hours at CDC.

Recommendation
1: Smallpox Vaccination

Because
of the small quantities of vaccine and vaccinia immune globulin (VIG)
maintained by CDC, a preventive vaccination program is not an option
at this time.

VIG is
recommended to treat severe cutaneous reactions to vaccination. It is
estimated that 250 of every 1 million persons vaccinated might require
VIG treatment.

Procedures

When
available, vaccination is normally done with a bifurcated needle.
A sterile needle is inserted into an ampoule of reconstituted vaccine
and, on withdrawal, a droplet of vaccine sufficient for vaccination
is held by capillarity between the two tines. The needle is held
at right angles to the skin; the wrist of the vaccinator rests against
the arm. Fifteen perpendicular strokes of the needle are rapidly
made in an area about 5 mm in diameter. The strokes should result
in a trace of blood at the site after 15-30 seconds. After vaccination,
excess vaccine should be wiped from the site with gauze that should
be discarded in a hazardous waste receptacle. The site should be
covered with a loose, nonocclusive bandage to deter the individual
from touching the site and perhaps transferring virus to other parts
of the body.

Efficacy

After
about 3 days, a red papule appears at the vaccination site and becomes
vesicular on about day 5. By day 7, it becomes the typical Jennerian
pustule—whitish, umbilicated, multilocular, containing turbid lymph
and surrounded by an erythematous areola that may continue to expand
for 3 more days. Regional lymphadenopathy and fever is not uncommon.
As many as 70 percent of children have 1 or more days of temperature
higher than 39°C (100°F) between days 4 and 14. The pustule gradually
dries, leaving a dark crust, which normally falls off after 3 weeks.

Successful
vaccination for those with partial immunity may manifest responses
along a gradient from that described above to an accelerated reaction
in which there is little more than a papule surrounded by erythema
that reaches a peak within 3-7 days.

A
response that peaks in erythema within 48 hours represents a hypersensitivity
reaction and does not signify that virus growth has occurred. Revaccination
is indicated.

Complications

The
frequency of complications with the vaccine used throughout the
United States and Canada (the New York Board of Health strain) is
the lowest for any vaccinia virus strain, but the risks are not
inconsequential.

Complications
can include postvaccinal encephalitis, progressive vaccinia (vaccinia
gangrenosa), eczema vaccinatum, generalized vaccinia, inadvertent
inoculation, and a variety of other complications, usually rashes.

Contraindications

Groups
at special risk for complications include persons with eczema or
other significant exfolliative conditions; patients with leukemia,
lymphoma, or generalized malignancy who are receiving therapy with
alkylating agents, antimetabolites, radiation, or large doses of
corticosteroids; patients with HIV infection; persons with hereditary
immune disorders; and pregnant women. If available, VIG may be given
simultaneously with vaccination in a dose of 0.3 mL/kg body weight.
If VIG is not available, vaccination may still be warranted, given
the far higher risk of an adverse outcome from smallpox than from
vaccination.

VIG
may also be administered to patients with progressive vaccinia,
eczema vaccinatum, severe generalized vaccinia, and periocular infections
resulting from inadvertent inoculation. It is administered in a
dose of 0.6 mL/kg body weight, given intramuscularly in divided
doses over a 24-to-36-hour period and may be repeated in 2 to 3
days if improvement does not occur. Because VIG quantities are limited,
it should be reserved for the most serious cases.

Immunity

The
immune status of those vaccinated more than 34 years ago is not
clear. Studies done on those remotely vaccinated have demonstrated
persistence of T-cell and humoral responses, but absolute levels
of neutralizing antibodies decline substantially during a 5-to-10-year
period post-vaccination. Epidemiologic studies during endemic smallpox
suggested (remote) vaccination could ameliorate disease but did
not prevent disease in a majority of cases with high-risk exposures.

Vaccine
Stockpile

CDC has contracted with Acambis to provide and maintain the SNS stockpile of ACAM2000 which is their vero cell derived live vaccinia virus smallpox vaccine.

Recommendation
2: Therapy

No antiviral
substances have proven effectiveness for smallpox treatment.

Vaccination
administered within 4 days of first exposure has been shown to offer
some protection against acquiring infection and significant protection
against a fatal outcome.

Currently
there is no cure for smallpox. Smallpox patients should be offered supportive
therapy plus antibiotics as indicated to treat occasional secondary
bacterial infections.

As soon
as the diagnosis of smallpox is made, all those suspected of being infected
should be immediately isolated and all persons in the household and
others who have had face-to-face contact with the infected individual
after the onset of fever should be vaccinated and placed under surveillance.
Patients should be isolated while infectious.

Because
persons who have had contact with an infected individual would not be
contagious until the onset of rash, they should take their temperatures
at least once daily, preferably in the evening. Any temperature higher
than 38°C or 101°F during the 17-day period following last exposure
to the infected patient would suggest the possible development of smallpox.
This would be cause for immediate isolation until it can be determined
clinically and/or by laboratory examination whether the person has smallpox.

Cooperation
from most patients and persons who have had contact with patients can
likely be ensured through counseling and persuasion. There may be some
for whom forcible quarantine is required.

In the
event of an outbreak, the following high-risk groups should be given
priority for vaccination: 1) persons exposed to the initial release
of the virus; 2) contacts of suspected or confirmed smallpox patients;
3) personnel selected for direct medical or public health evaluation,
care, or transportation of suspected or confirmed smallpox patients;
4) laboratory workers selected for the collection or processing of possible
smallpox specimens; 5) other persons who may be in contact with infectious
material, such as hospital laundry or medical waste, and mortuary workers;
6) other groups essential to response activities such as selected law
enforcement, emergency response, or military personnel; and 7) all individuals
present at a hospital during the time that a smallpox patient is present
and not isolated appropriately. Employees for whom vaccination would
be contraindicated should be furloughed.

In the
event of a limited outbreak, patients should be admitted to the hospital
and confined to rooms that are under negative pressure and equipped
with high-efficiency particulate air (HEPA) filtration.

To limit
nosocomial infections, authorities should consider designating a specific
hospital or hospitals for smallpox care.

Standard
precautions using gloves, gowns, and masks should be observed. All laundry
and waste should be placed in biohazard bags and autoclaved before being
laundered or incinerated. Surfaces that may be contaminated with smallpox
virus can be decontaminated with disinfectants that are used for standard
hospital infection control, such as hypochlorite and quaternary ammonia.

Patients
who die should be cremated whenever possible.

Recommendation
5: Additional Research Needs

Priority
should be given to three areas: vaccines, immunotherapy and drugs, and
diagnostics.